Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable renal disease progression, which is primarily due to genetic heterogeneity (PKD1 vs. PKD2). Evidence obtained in murine models and studies of variability in siblings and twins suggest that modifier genes influence renal disease progression in ADPKD. These modifier loci could affect cystogenesis and/or cyst progression, but also more general factors, i.e. endothelial dysfunction. The demonstration of endothelial dysfunction in Pkd1(+/-) mice and ADPKD patients, and the effect of the frequent Glu298Asp polymorphism of ENOS on renal disease progression in ADPKD suggest that an impaired release of nitric oxide (NO) by endothelial cells can accelerate renal function degradation. These results also suggest that polycystins can participate in the regulation of endothelial NO synthase (eNOS) and that addressing endothelial dysfunction in ADPKD can offer a new perspective to slow renal disease progression.